Curcuma aromatica derived single-atom carbon dots with microenvironment responsible multi-enzyme activity for infected diabetic wound regeneration

Group B Streptococcus (GBS) is a Gram-positive pathobiont that can cause adverse health outcomes in neonates and vulnerable adult populations. GBS is one of the most frequently isolated bacteria from diabetic (Db) wound infections but is rarely found in the non-diabetic (nDb) wound environment. Previously, RNA sequencing of wound tissue from Db wound infections in leprdb diabetic mice showed increased expression of neutrophil factors, and genes involved in GBS metal transport such as the zinc (Zn), manganese (Mn), and putative nickel (Ni) import systems. Here, we develop a Streptozotocin-induced diabetic wound model to evaluate the pathogenesis of two invasive strains of GBS, serotypes Ia and V. We observe an increase in metal chelators such as calprotectin (CP) and lipocalin-2 during diabetic wound infections compared to nDb. We find that CP limits GBS survival in wounds of non-diabetic mice but does not impact survival in diabetic wounds. Additionally, we utilize GBS metal transporter mutants and determine that the Zn, Mn, and putative Ni transporters in GBS are dispensable in diabetic wound infection but contributed to bacterial persistence in non-diabetic animals. Collectively, these data suggest that in non-diabetic mice, functional nutritional immunity mediated by CP is effective at mitigating GBS infection, whereas in diabetic mice, the presence of CP is not sufficient to control GBS wound persistence. IMPORTANCE Diabetic wound infections are difficult to treat and often become chronic due to an impaired immune response as well as the presence of bacterial species that establish persistent infections. Group B Streptococcus (GBS) is one of the most frequently isolated bacterial species in diabetic wound infections and, as a result, is one of the leading causes of death from skin and subcutaneous infection. However, GBS is notoriously absent in non-diabetic wounds, and little is known about why this species thrives in diabetic infection. The work herein investigates how alterations in diabetic host immunity may contribute to GBS success during diabetic wound infection.

The wound healing and antimicrobial effects of Azadirachta indica leaf extracts were evaluated on Eschericha coli infected diabetic wounds using albino rat model. The study was a cross-sectional work done between January and June, 2020. Eschericha coli was isolated and identified from 50 infected diabetic patients using Eosin methylene blue and standard biochemical tests. The crude extracts of A. indica were gotten using ethanol and water by soxhlet method. The phytochemical such as saponins, phenols, tannins, flavonoid and alkaloids were determined quantitatively and qualitatively using standard method. In vitro antimicrobial effect of extracts and their combination were evaluated. The wound healing effects of the extracts were done using six weeks old albino rat model. Out of 50 swab samples of infected diabetic wounds, 30 isolates were obtained which E. coli was 20% of the bacterial isolates from the infected wound. The phytochemical analysis of the extracts showed the presence of saponin, flavonoids, steroid, alkaloids, tannins and phenol. Among the leaf extracts analysed, A. indica ethanol extract has the highest inhibition zone against E. coli (10.67±1.15 mm) at 500 mg/ml and 1000 mg/ml concentration. The Minimum inhibitory concentration (MIC) was 250 mg/ml while the Minimum Bactericidal Concentration (MBC) was 1000mg/ml. Diabetic and healthy groups of albino rats were treated after 1 week of infection. Comparing the negative control rats witsh those treated with daily topical application of the leaf extracts, showed significant reduction in wound size and rapid healing (P = 0.05). Comparing with positive control, the leaf extracts have almost the same healing effect with the positive control (povidone iodine). The leaf extracts of A. indica possess antimicrobial properties for E. coli especially the ethanol extract which heals faster than aqueous extract and can be used as an alternative for healing infected non diabetic and chronic diabetic wounds.

Infected diabetic foot ulcers (iDFUs) cause great concern, as they generally heal poorly and are precursive of diabetic-related foot amputation and even death. Scientists have tested various techniques in attempts to ascertain the best treatment for iDFUs; however, the results have remained inconclusive. Stem cell therapy (SCT) appears to improve iDFU through its antimicrobial impacts, yet cogent information regarding the repair of iDFUs with SCT is lacking. Herein, published articles are evaluated to report coherent information about the antimicrobial effects of SCT on the repair of iDFUs in diabetic animals and humans. In this systematic review, we searched the Scopus, Medline, Google Scholar, and Web of Science databases for relevant full-text English language articles published from 2000 to 2022 that described stem cell antimicrobial treatments, infected diabetic wounds, or ulcers. Ultimately, six preclinical and five clinical studies pertaining to the effectiveness of SCT on healing infected diabetic wounds or ulcers were selected. Some of the human studies confirmed that SCT is a promising therapy for diabetic wounds and ulcers. Notably, more controlled studies performed on animal models revealed that stem cells combined with a biostimulator such as photobiomodulation decreased colony forming units and hastened healing in infected diabetic wounds. Moreover, stem cells alone had lower therapeutic impact than when combined with a biostimulant.

Efficient management of difficult-to-heal diabetic wounds remains a clinical challenge owing to bacterial infections, as well as oxidative and hyperglycemic complex pathology. Therefore, developing intelligent strategies for diabetic wound healing is urgently needed. Herein, an ultrasound (US)-responsive microneedle (MN) patch (MN@GOX@TiO2-X@CO) capable of controlled delivery of carbon monoxide (CO) gas within the skin for effective treatment of diabetic infected wounds is developed. Benefiting from the specific form of microneedle (MN) patch, sonosensitizer (TiO2-X), •OH-responsive CO prodrug (MPA-CO), and glucose oxidase (GOX) can be loaded together and effectively delivered to infectious wounds. With the semi-fluidic hyaluronic acid (HA) coating under the physiological condition, CO could be released efficiently in situ and directly acted on infected wound tissue upon US triggering. Both in vitro and in vivo results showed that US-triggered CO release from MN@GOX@TiO2-X@CO not only effectively inhibited the S. aureus and MRSA infection but also promoted fibroblasts proliferation and migration under hyperglycemic physiology, thereby accelerating diabetic wound healing. Collectively, the approach effectively addresses the impaired skin regeneration function in diabetic wounds and offers a promising therapeutic strategy for the efficient healing of infected diabetic wounds.

Accurately orchestrated course of events normally observed in healing are not followed in diabetic wounds, and bacterial colonization/infection further messes up the process. Novel therapeutic options for treatment of infections caused by multidrug-resistant Staphylococcus aureus are urgently needed. HAMLET (human α-lactalbumin made lethal to tumor cells) has been reported to be able to sensitize bacterial pathogens to traditional antimicrobial agents. The aim was to assess the wound healing activity of curcumin nanoparticles in diabetic wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) sensitized with HAMLET. Fifty male rats were randomized into 5 groups of 10 animals each. In CONTROL group, 0.1-mL sterile saline 0.9% solution was added to the wounds with no infection. In MRSA group, the wounds were infected with MRSA and only treated with 0.1-mL sterile saline 0.9% solution. In MRSA/HAMLET group, infected wounds were treated with HAMLET (100 µg). In MRSA/CNP group, animals with infected wounds were treated with 0.1 mL topical application of 1 mg/mL curcumin nanoparticles. In MRSA/CNP/HAMLET group, animals with infected wounds were treated with topical application of 0.1 mL solution of curcumin nanoparticles (1 mg/mL) and HAMLET (100 µg). All test formulations were applied for 10 days, twice a day, starting from first treatment. Microbiological examination; planimetric, biochemical, histological, and quantitative morphometric studies; immunohistochemical staining for angiogenesis; determination of hydroxyproline levels; and reverse transcription polymerase chain reaction for caspase 3, Bcl-2, and p53 showed that there was significant difference between animals in MRSA/CNP/HAMLET group compared with other groups (P < .05). Curcumin nanoparticles improved diabetic wounds infected with MRSA sensitized with HAMLET and had the potential to offer more attention to this safer agent for topical use in infected diabetic wounds.

Infectious diabetic wounds present a substantial challenge, characterized by inflammation, infection, and delayed wound healing, leading to elevated morbidity and mortality rates. In this work, we developed a multifunctional lipid nanoemulsion containing quercetin, chlorine e6, and rosemary oil (QCRLNEs) for dual anti-inflammatory and antibacterial photodynamic therapy (APDT) for treating infectious diabetic wounds. The QCRLNEs exhibited spherical morphology with a size of 51 nm with enhanced encapsulation efficiency, skin permeation, and localized delivery at the infected wound site. QCRLNEs with NIR irradiation have shown excellent wound closure and antimicrobial properties in vitro, mitigating the nonselective cytotoxic behavior of PDT. Also, excellent biocompatibility and anti-inflammatory and wound healing responses were observed in zebrafish models. The infected wound healing properties in S. aureus-infected diabetic rat models indicated re-epithelization and collagen deposition with no signs of inflammation. This multifaceted approach using QCRLNEs with NIR irradiation holds great promise for effectively combating oxidative stress and bacterial infections commonly associated with infected diabetic wounds, facilitating enhanced wound healing and improved clinical outcomes.

ObjectiveA large body of literature has demonstrated the significant efficacy of antibiotic bone cement in treating infected diabetic foot wounds, but there is less corresponding evidence-based medical evidence. Therefore, this article provides a meta-analysis of the effectiveness of antibiotic bone cement in treating infected diabetic foot wounds to provide a reference basis for clinical treatment.MethodsPubMed, Embase, Cochrane library, Scoup, China Knowledge Network (CNKI), Wanfang database, and the ClinicalTrials.gov were searched, and the search time was from the establishment of the database to October 2022, and two investigators independently. Two investigators independently screened eligible studies, evaluated the quality of the literature using the Cochrane Evaluation Manual, and performed statistical analysis of the data using RevMan 5.3 software.ResultsA total of nine randomized controlled studies (n=532) were included and, compared with the control group, antibiotic bone cement treatment reduced the time to wound healing (MD=-7.30 95% CI [-10.38, -4.23]), length of hospital stay (MD=-6.32, 95% CI [-10.15, -2.48]), time to bacterial conversion of the wound (MD=-5.15, 95% CI [-7.15,-2.19]), and the number of procedures (MD=-2.35, 95% CI [-3.68, -1.02]).ConclusionAntibiotic bone cement has significant advantages over traditional treatment of diabetic foot wound infection and is worthy of clinical promotion and application.Systematic review registrationPROSPERO identifier, CDR 362293.

Although near‐infrared (NIR) light‐based photothermal therapies have shown therapeutic potential for infected wounds, the attenuation of NIR light intensity in tissue has severely limited the usage in deep bacterial infections. Herein, magneto‐thermal responsive bilayer microneedles (Fe‐Se‐HA MNs) consisting of functionalized hyaluronic acid (HA), ferro‐ferric oxide (Fe3O4), and micelle‐protected selenium nanoparticles (SeNPs@LAS) are constructed to overcome this challenge based on a self‐designed disk‐shaped electromagnetic field device (Disk‐ZVS). The electromagnetic field generated by the Disk‐ZVS shows virtually no intensity attenuation in living tissue. Finite element simulations showed that the field intensity and electromagnetic loss are concentrated on the tips of Fe‐Se‐HA MNs. The MNs are able to puncture hard scabs, penetrate into bacterial biofilms, and perform effective magnetic‐thermal conversion for deep hyperthermia sterilization. Following, the Fe‐Se‐HA MNs can be gradually degraded by excessive hyaluronidase in diabetic wound to release SeNPs, which reduce reactive oxygen species (ROS) to regulate wound redox homeostasis. Meanwhile, the SeNPs are beneficial to angiogenesis, which facilitates blood vessel formation and promotes wound repair. Therefore, various functions can be achieved for the Fe‐Se‐HA MNs, such as magneto‐thermal disinfection, deep and non‐invasive tissue penetration, anti‐inflammation, and pro‐angiogenesis, which shows great potential as an adjunctive therapy for infected diabetic wounds.

The regeneration and repair of diabetic wounds, especially those including bacterial infection, have always been difficult and challenging using current treatment. Herein, an effective strategy is reported for constructing glucose-responsive functional hydrogels using nanocomposites as nodes. In fact, tannic acid (TA)-modified ceria nanocomposites (CNPs) and a zinc metal-organic framework (ZIF-8) were employed as nodes. Subsequent crosslinking with 3-acrylamidophenylboronic acid achieved functional nanocomposite-hydrogels (TA@CN gel, TA@ZMG gel) by radical-mediated polymerization. Compared with a simple physically mixed hydrogel system, the mechanical properties of TA@CN gel and TA@ZMG gel are significantly enhanced due to the intervention of the nanocomposite nodes. In addition, this kind of nanocomposite hydrogel can realize the programmed loading of drugs and release of drugs in response to glucose/PH, to coordinate and promote its application in the regeneration and repair of diabetic wounds and infected diabetic wounds. Specifically, TA@CN gel can remove reactive oxygen species and generate oxygen through its various enzymatic activities. At the same time, it can effectively promote neovascularization, thus promoting the regeneration and repair of diabetic wounds. Furthermore, glucose oxidase-loaded TA@ZMG gel exhibits glucose response and pH-regulating functions, triggering programmed metformin (Met) release by degrading the metal-organic framework (MOF) backbone. It also exhibited additional synergistic effects of antibacterial activity, hair regeneration and systemic blood glucose regulation, which make it suitable for the repair of more complex infected diabetic wounds. Overall, this novel nanocomposite-mediated hydrogel holds great potential as a biomaterial for the healing of chronic diabetic wounds, opening up new avenues for further biomedical applications.

A multifunctional nanomaterial based wound healing matrix was fabricated by modified co-precipitation and chemical reduction method. The matrix was comprised of either a bimetallic Fe-Cu nanocomposite powder or a wound bed made up of absorbent cotton swab impregnated with bimetallic Fe-Cu nanocomposite. The detailed analytical studies of both dressing materials (powder and cotton bed) were carried out with transmission electron microscopy, X-ray diffraction, field emission scanning electron microscopy, energy-dispersive X-ray, and bright field microscopy. Both the nanocomposite powder and the nanocomposite impregnated cotton swab exhibited antimicrobial activity against Gram positive and Gram negative bacteria, including multidrug-resistant bacteria (such as methicillin-resistant Staphylococcus aureus) as well as against fungus isolated from different human biological samples (pus/tissue culture/urine). For real time applications, the in vivo wound healing ability of both dressing materials was also carried out in Wistar albino rats with infected diabetic wounds. These biocompatible and biodegradable dressing materials with broad-spectrum antimicrobial properties have exhibited more than 20 mm in diameter zone of microbial growth inhibition against several types of microbes. Remarkably, they have also been found to assist in healing of infected diabetic wounds and show a prospect in the management of other infectious wounds.

Diabetes is a prevalent chronic metabolic disorder, and wound infection represents one of its most common and severe complications─frequently leading to lower-limb amputation. Accelerating the healing of diabetic wounds remains a significant clinical challenge. Conventional wound dressings often necessitate frequent, complex dressing changes that exacerbate patient discomfort and risk secondary tissue damage. To address these limitations, we developed a multifunctional hydrogel (designated Shi-Mg@CAPLL) by integrating a shikonin-loaded magnesium-based metal-organic framework (Shi-Mg) into a colanic acid/ε-polylysine (ε-PLL) hydrogel matrix (CAPLL). Leveraging the synergistic antibacterial effects of ε-PLL and shikonin, Shi-Mg@CAPLL effectively suppresses both bacterial and fungal colonization in infected wounds. Moreover, the sustained release of bioactive components (Mg2+, shikonin) confers potent antioxidant, anti-inflammatory, and angiogenic properties, facilitating complete tissue regeneration by day 16. Our results demonstrate that Shi-Mg@CAPLL offers a promising therapeutic strategy for managing infected diabetic wounds and promoting their healing.

Reduced Bioactive Microbial Products (Pathogen-Associated Molecular Patterns) Contribute to Dysregulated Immune Responses and Impaired Healing in Infected Wounds in Mice with Diabetes

Glucose metabolism-inspired catalytic patches for NIR-II phototherapy of diabetic wound infection.

Dual cross-linked organic-inorganic hybrid hydrogels accelerate diabetic skin wound healing

Multifunctional hydrogel with reactive oxygen species scavenging and photothermal antibacterial activity accelerates infected diabetic wound healing